New therapeutic options are needed for NHL because more than two thirds of patients fail to achieve long-term disease free-survival. Despite a therapeutic index of only 10-30, conventional RIT has proven especially effective for NHL, when CD20, CD22 or Lym-1 MAbs have been used as the targeting molecule carrier for 131I, 67Cu, or 90Y in a nonmyeloablative strategy. Dose intensification incorporating BMT in a myeloablative strategy using 90Y-DOTA-peptide -Lym-1 having a biodegradable peptide linker modestly improved the therapeutic index and led us to appreciate the complexities involved in CMRIT. In preclinical studies, Taxol synergized RIT and CD22 MAb was found promising for immunotherapy. Both of these agents are under study by colleagues under other grants. We have shown that the HLA-DR epitope for Lym-1 MAb is a particularly attractive target because it is present on almost all malignant B cells and at much greater density than on normal B cells. Through interactions with colleagues at LLNL, unique opportunities have arisen to improve the therapeutic index 10-100 times using novel approaches to develop synthetic, small molecule high-affinity ligands (SHALs) that can better fulfill the potential of RIT by mimicking 131I-iodide in thyroid cancer, the prototype for RIT. The HLA-DR10 surface protein on malignant B cells has been chosen as a target because our wealth of information on it has convinced us of its attractiveness as a target in patients with NHL and CLL. Characterization of the Lym-1 epitope on HLA-DR identified binding sites especially attractive because of evidence for preferential binding to malignant lymphocytes when compared to normal lymphocytes. These binding sites will be used to model, design and generate synthetic molecules of high selectivity and binding to the HLA-DR of malignant lymphomas and leukemias. We have synthesized our first five bidentate SHALs and determined that at least one of these SHALs binds to isolated HLA-DR10 with a Kd of approximately 20nM. Preliminary experiments show this SHAL binds to human lymphoma cells and tissue, competes for binding to the same site as Lym-I and does not bind to other malignant cell lines. This natural extension of our ongoing translational activities, involving HLA-DR as a target for radioisotopic carrier molecules to deliver systemic radiotherapy, affords an opportunity to dose-intensify by dramatically improving the therapeutic index. This project has, and will continue to interact extensively with the Molecular Modeling group, the Pharmacy group and the Pharmacokinetics/Dosimetry group.